Effect of priming interval on reactogenicity, peak immunological response, and waning after homologous and heterologous COVID-19 vaccine schedules: exploratory analyses of Com-COV, a randomised control trial.

BACKGROUND: Priming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com-COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca). METHODS: Com-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020-005085-33). FINDINGS: Between Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77-89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS-CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4-week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2-ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1·4 (95% CI 1·1-1·8) for homologous BNT162b2, 1·5 (1·2-1·9) for ChAdOx1 nCoV-19-BNT162b2, 1·6 (1·3-2·1) for BNT162b2-ChAdOx1 nCoV-19, and 2·4 (1·7-3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17-0·24 of the 28-day post-second dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19-BNT162b2 were up to 80% less reactogenic than 4-week schedules. INTERPRETATION: These data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals. FUNDING: UK Vaccine Taskforce and National Institute for Health and Care Research.

Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial.

BACKGROUND: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer-BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. METHODS: Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. FINDINGS: Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. INTERPRETATION: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. FUNDING: UK Vaccine Task Force and National Institute for Health Research.

SKread predicts handwriting performance in patients with low vision.

OBJECTIVE: To assess whether performance on the Smith-Kettlewell Reading (SKread) test is a reliable predictor of handwriting performance in patients with low vision. DESIGN: Cross-sectional study. PARTICIPANTS: Sixty-six patients at their initial low-vision rehabilitation evaluation. METHODS: The patients completed all components of a routine low-vision appointment including logMAR acuity, performed the SKread test, and performed a handwriting task. Patients were timed while performing each task and their accuracy was recorded. The handwriting task was performed by having patients write 5 5-letter words into sets of boxes where each letter is separated by a box. The boxes were 15 × 15 mm, and accuracy was scored with 50 points possible from 25 letters: 1 point for each letter within the confines of a box and 1 point if the letter was legible. Correlation analysis was then performed. RESULTS: Median age of participants was 84 (range 54-97) years. Fifty-seven patients (86%) had age-related macular degeneration or some other maculopathy, whereas 9 patients (14%) had visual impairment from media opacity or neurologic impairment. Median Early Treatment Diabetic Retinopathy Study acuity was 20/133 (range 20/22 to 20/1000), and median logMAR acuity was 0.82 (range 0.04-1.70). SKread errors per block correlated with logMAR acuity (r = 0.6), and SKread time per block correlated with logMAR acuity (r = 0.51). SKread errors per block correlated with handwriting task time/accuracy ratio (r = 0.61). SKread time per block correlated with handwriting task time/accuracy ratio (r = 0.7). LogMAR acuity score correlated with handwriting task time/accuracy ratio (r = 0.42). All p values were < 0.01. CONCLUSIONS: SKread scores predict handwriting performance in patients with low vision better than logMAR acuity.

Random word recognition chart helps scotoma assessment in low vision.

PURPOSE: To evaluate the use of SKread, a vision test based on random word sequences that prevents the prediction of upcoming words by linguistic criteria and is simple to score in a clinical setting. METHODS: SKread combines the standardized format of the MNread test with sequences of random words and letters like the Pepper Visual Skills for Reading test. A total of 231 subjects (aged 16 to 97 years) participated. We report data from 136 eyes of subjects with a maculopathy and 65 with normal or near-normal vision. Test reliability was investigated on an additional 30 eye-healthy subjects. We tested visual acuity and reading performance for continuous text and random words monocularly. Reading speed and all errors made are reported. RESULTS: Reading speed was always higher for continuous text than for random word sequences, even in normally sighted subjects for whom the median reading times per paragraph were 2.4 s (MNread) vs. 6.8 s (SKread). In patients with maculopathies, the medians were 4.2 s vs. 12.25 s. These differences were statistically significant. Number and type of errors made depended only negligibly on age and visual acuity. Patients with a dense scotoma right of fixation made more "right errors" by missing letters at the end of words, whereas those with a scotoma left of fixation made more "left errors" by missing letters at the beginning of words. The SKread test showed good test-retest repeatability. CONCLUSIONS: The unpredictability of random word and letter sequences renders reading performance highly dependent on eyesight and less dependent on reading skill and educational level. Recurrent right or left errors can indicate the presence and location of a scotoma without expensive equipment. This knowledge can be used to teach patients about how the scotoma can interfere with their vision.

Comparison of traditional versus high-fidelity simulation in the retention of ACLS knowledge.

OBJECTIVE: We performed a single-blinded, randomized controlled trial to evaluate the retention of advanced cardiac life support (ACLS) knowledge between high-fidelity simulation training (HFST) and traditional training (TT) in medical students. METHODS: Medical students were randomized to HFST or TT for their ACLS training. Students were then tested on 2 different mega-code scenarios immediately after their training and then 1-year later. A survey was performed asking their satisfaction of ACLS training and confidence of ACLS knowledge with a 10-point rating scale. RESULTS: 93 students were randomized with 86 completing the study (HFST=45, TT=41). The HFST group scored a higher percentage correct on initial testing than the TT group (83% vs. 70%, P<0.0001). However at 1-year follow up, both groups performed the same (66% vs. 66%, P=0.84). Satisfaction with training was higher with the HFST compared to the TT group (9.0 vs. 7.8, P<0.0001). Confidence in ACLS knowledge between HFST and TT groups were similar at baseline (6.9 vs. 6.5, P=0.18) and at 1-year (4.8 vs. 4.5, P=0.46). CONCLUSION: Students demonstrated greater ACLS knowledge initially with HFST than with TT. However, after 1-year, both groups performed the same. Satisfaction with training was higher with HFST compared to TT. Confidence in ACLS knowledge was the same initially and decreased similarly over a 1-year time period regardless of the type of ACLS training. Further studies will need to determine optimal strategies to retain ACLS knowledge.

Comparison of the immunogenicity of vaccines prepared from viable Mycobacterium bovis BCG, heat-killed Mycobacterium leprae, and a mixture of the two for normal and M. leprae-tolerant mice

Intradermal vaccines consisting of viable Mycobacterium bovis BCG, heat-killed Mycobacterium leprae, or mixtures of the two were titrated in mice in doses of 10(5.2), 10(5.8), 10(6.4), 10(7.0), and 10(7.6) acid-fast bacilli. The immune response was measured by sensitization (48 to 72 h foot pad enlargement on challenge with 10(7.0) heat-killed M. leprae) and by protection against infection with a viable M. leprae challenge. There was increasing response with increasing dose of vaccine, and overall the responses to the three vaccines were similar. At the lowest dose, however, the combination of BCG and M. leprae gave superior protection. The local reaction to the vaccines in the lower dose range was less severe with the M. leprae vaccine. In another experiment, the three vaccines were compared in normal mice and in mice that had been rendered tolerant by intravenous injection of M. leprae. The tolerant mice developed no measurable sensitization on vaccination with M. leprae, but they developed partial but distinct sensitization on vaccination with BCG, alone or in combination with M. leprae. The tolerant mice developed little or no protection with any of the vaccines, however..

Searches among mycobacterial cultures for antileprosy vaccines

All mycobacteria species share some antigens, so there may be cultivable mycobacterial cultures that can provide vaccine protection against leprosy. Vaccine protection against Mycobacterium leprae infections in mice has been demonstrated for M. leprae itself, as living or heat-killed suspensions, and for Mycobacterium bovis (BCG), as living suspensions. Results are reported here with 17 other cultures. The mycobacterial suspensions were injected intradermally, and the mice were challenged in the footpad with infectious suspensions of M. leprae. In two experiments the mice were also challenged by footpad injections of 10(7) heat-killed M. leprae so the footpad enlargment could be measured. That some mycobacterial suspensions were immunogenic for some of their own antigens was suggested by reactions at the vaccine site and enlargement of the regional lymph nodes. Some mycobacterial suspensions also stimulated footpad enlargement on challenge by homologous suspensions or by challenge with M. leprae suspensions. Consistent protection against infectious challenge with M. leprae was observed only with BCG and M. leprae, however...

Heat stability of Mycobacterium leprae immunogenicity

The protection provided to mice by vaccines administered intradermally was measured after footpad challenge with Mycobacterium leprae. The protection offered by M. leprae suspensions was not decreased when the vaccines were killed by 60 degrees C heat or at the higher temperatures tested, which included 215 degrees C (autoclave). Even highly purified suspensions retained their immunogenicity. In contrast, the vaccine protection provided by intradermal M. bovis (strain BCG) was markedly reduced when heated to 60 degrees C. The enlargement of the lymph nodes regional to the intradermal vaccines was measured and found generally to parallel the vaccine protection provided by M. leprae and by BCG.

Kinetic testing of drugs against Mycobacterium leprae in mice. Activity of cephaloridine, rifampin, streptovaricin, vadrine, and viomycin

A series of drugs that had been found active against Mycobacterium leprae in mice by the continous method of drug administration was tested by the kinetic method. Vadrine and vyomivin were found inactive. Cephaloridine, streptovaricin, and rifampin gave bactericidal-type results. In a second experiment, rifampin was found to have distinct bactericidal effect when given for only 2 days. The plasma levels of rifampin that were associated with bactericidal effect in mice were in the range reported for man receiving acceptable dosages of rifampin. Cephaloridine and, especially, rifampin merit further investigation in clinical trials in leprosy patients, either as single drugs or in combination with other active drugs. The combination of rifampin and dapsone (DDS) or acedapsone (DADDS) appear to provide the advantages of tboth drugs.